The Basal Ganglia (BG) include the caudate nucleus, putamen, globus pallidus, subthalamic nucleus and the substantia nigra. These structures are mutually interconnected and participate in similar functions. The hallmarks of BG diseases are various motor disturbances, such as involuntary movements and changes in muscle tone which stress the BG involvement in the central control of movement. It is generally assumed that the control of motor functions is mediated through the pallido- thalamo-cortical and nigro-thalamo-cortical circuits. Anatomical data support this concept but they also indicate that this may not be the only route since a portion of BG outflow is directed toward the brainstem. It is the long-range goal of our research to clarify the anatomical organization of BG projections to the brainstem, and to understand how these connections are integrated into known functional systems of the CNS. A major source of the brainstem projections is the pars reticulata of the substantia (SNR). The SNR is known to be involved in the control of eye and head/neck movements through the connections with the optic tectum. However, in spite of recent advances in BG research, the anatomical organization and significance of other SNR outflow to the brainstem remain to be elucidated. The objectives of this proposal proceed from our previous studies focused on the nucleus tegmenti pedunculopontinus (PPN) and continue to pivot about a central goal, i.e. to elucidate the pathways linking the SNR to the brainstem structures connected with the spinal cord. The proposed light and electron microscopic studies exploit a new technique which combines anterograde transport of Phaseolus vulgaris-leucoaglutinin (PHA-L) with retrograde transport of Cholera toxin subunit beta (CTB) or Fluoro-Gold (FG). The advantages of this technical combination include a demonstration of anterogradely labeled fibers and retrogradely labeled cells in contrasting colors within the same preparation which can be further processed for electron microscopy. Furthermore, each of these tracing techniques can be combined with transmitter-specific immunohistochemistry. Specifically, it is proposed to: 1) determine whether the nigral input to the PPN terminates on both cholinergic and non-cholinergic cells; 2) determine on light and electron microscopic levels the termination of PPN fibers onto the reticulospinal neurons projecting to the cervical, thoracic and lumbar cord; 3) confirm electron microscopically that the nigral fibers terminate on the spinal cord- projecting neurons within the nuclei associated with the medial longitudinal fasciculus and within the tuberal lateral hypothalamic area. The output pathways of the BG which bypass the cerebral cortex might be of importance in humans, not only in normal motor behavior but also, and even more so, in abnormal motor behavior such as Huntington's chorea and some symptoms of Parkinson's disease. Furthermore, disruption of possible connections linking the SNR to the visceromotor system may account for autonomic disorders that accompany some forms of Parkinson's disease.